Ambro van Hoof, Ph.D.
I was born and raised in the Netherlands. I first learned about molecular genetics during my undergraduate education at Wageningen Agricultural University. I decided to pursue molecular genetics for my graduate education at the DOE Plant Research Lab at Michigan State University. During my graduate work I studied mRNA quality control and degradation pathways in plants. After receiving my PhD, I continued studying mRNA degradation pathways, but switched to using yeast because of the better experimental tools available, and because yeast is more closely related to humans. These post-doctoral studies led me to the RNA exosome, and I have been fascinated by its functions ever since.
- Postdoctoral Fellow
- Howard Hughes Medical Institute; University of Arizona
- Michigan State University, 1997
mRNA degradation and quality control of gene expression
Gene expression is a complex process that all life forms need to carry out in a precisely controlled fashion. The degradation of mRNA serves important roles in this process. For example degradation rates of individual mRNAs can be regulated and affect mRNA abundance, and thus how much of each protein is produced by translation. mRNA decay also plays an important role in maintaining the overall fidelity of gene expression by preferentially degrading aberrant mRNAs that are made by mistakes during mRNA processing reactions. One example of aberrant mRNAs that are extremely rapidly degraded are those that lack a stop codon. Such “nonstop” mRNAs are produced frequently by premature addition of a poly(A) tail.
The yeast Saccharomyces cerevisiae and probably most other eukaryotes have two general pathways to degrade mRNA. These two pathways both degrade stable and unstable mRNAs. Thus, the key to understanding differential mRNA degradation is to understand the interactions of a particular mRNA with the basal machinery.
One of the two pathways of mRNA degradation is carried out by the exosome, a large complex containing ten different proteins. In addition to degrading mRNA, the exosome degrades many other aberrant RNAs, including misprocessed tRNAs and rRNA. It also functions in the maturation of many RNAs from 3′ extended precursors. This raises interesting questions such as why there are so many subunits in one complex, and how does the exosome completely degrade some RNAs, but process others.
Not surprisingly, defects in this multifunctional machine lead to a wide range of genetic diseases, including tricho-hepato-enteric syndrome, pontocerebellar hypoplasia, Perlman syndrome and cancer. On the other hand, inappropriate mRNA degradation by the exosome can cause diseases as diverse as Haemophilia or Reduced fertility, depending on which mRNA is targeted for degradation by the exosome. Our research on how the exosome carries out its multitude of functions provides insight into the molecular mechanisms behind these human diseases.
Marshall, A.N., Montealegre, M.C., Jimenez-Lopez, C., Lorenz, M.C., and van Hoof, A. (2013). Alternative splicing and subfunctionalization generates functional diversity in fungal proteomes. PLoS Genet 9, e1003376.
Klauer, A.A., and van Hoof, A. (2012). Degradation of mRNAs that lack a stop codon: a decade of nonstop progress. Wiley Interdiscip Rev RNA 3, 649-660.
Schaeffer, D., and van Hoof, A. (2011). Different nuclease requirements for exosome-mediated degradation of normal and nonstop mRNAs. Proc Natl Acad Sci U S A 108, 2366-2371.
Schaeffer, D., Tsanova, B., Barbas, A., Reis, F.P., Dastidar, E.G., Sanchez-Rotunno, M., Arraiano, C.M., and van Hoof, A. (2009). The exosome contains domains with specific endoribonuclease, exoribonuclease and cytoplasmic mRNA decay activities. Nature Struct Mol Biol 16, 56-62.
Meaux, S., van Hoof, A., and Baker, K.E. (2008). Nonsense-mediated mRNA decay in yeast does not require PAB1 or a poly(A) tail. Mol Cell 29, 134-140.